Role of adherens junction-associated membrane protein shrew-1 in polarized and non-polarized cells in vitro and in vivo

细胞迁移和细胞向周围组织的侵袭是正常发育和病理条件下的基本过程。在早期发育，特别是在神经和原肠胚形成期间，细胞获得迁移的间充质表型，与侵袭性肿瘤细胞不同。单细胞的侵袭往往与钙粘蛋白或含免疫球蛋白结构域的细胞粘附分子和调节蛋白的表达和功能变化有关，如蜗牛家族成员、转化生长因子β。我们发现了一种跨膜蛋白，shrew-1，它在细胞迁移和侵袭中起着核心作用。在上皮细胞中，shrew-1定位于粘附连接处。其定位和运输受表皮生长因子（EGF）和分散因子（SF/HGF）的影响，可能介导上皮形态的丧失、迁移和侵袭的增加以及这些因素诱导的细胞间粘附的减少。Shrew-1可能在上皮细胞的形态可塑性中起作用。我们建议通过计算、生物信息学分析、敲除或过表达该蛋白的野生型或突变变体来扩展我们对该分子特性的研究。细胞培养实验将辅以结合敲除技术和组织重建技术对小鼠乳腺发育过程中shrew-1功能的分析。

Cell migration and invasion of cells into the surrounding tissue are fundamental processes in normal development and pathological conditions. In early development, particularly during neurulation and gastrulation, cells acquire a migratory, mesenchymal phenotype, not unlike that of invasive tumor cells. The invasion of single cells is often correlated with changes in the expression and function of cadherins or immunoglobulin domain-containing cell adhesion molecules and regulatory proteins, e.g. snail family members, transforming growth factor beta. We have discovered a transmembrane protein, shrew-1, which plays a central role in cell migration and invasion. In epithelial cells, shrew-1 localizes to adherens junctions. Its localization and trafficking is responsive to epidermal growth factor (EGF) and scatter factor (SF/HGF) and may mediate the loss of epithelial morphology, increase of migration and invasion and decrease of intercellular adhesion induced by these factors. Shrew-1 may play a role in the morphological plasticity of epithelial cells. We are proposing to extend our studies of the properties of this molecule by computational, bioinformatic analyses, knockdown or overexpression of wildtype or mutant variants of the protein. Cell culture experiments will be complemented by an analysis of shrew-1 function in the development of the mouse mammary gland combining knock-down technology and tissue reconstitution techniques.